Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine

ABSTRACT

3-(3-chloro-1H-pyrazol-1-yl)pyridine is prepared by cyclizing 3-hydrazinopyridine.dihydrochloride with a dialkyl maleate to provide an alkyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate, by chlorinating to provide an alkyl 3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate, by oxidizing to provide an alkyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate, by converting the ester to the carboxylic acid by hydrolysis to provide 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride, and by removing the carboxylic acid by a decarboxylation reaction.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/039,128, filed Aug. 19, 2014, the entiredisclosure of which is hereby expressly incorporated by reference inthis Application.

BACKGROUND

The present invention concerns an improved process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine.

US 20130288893(A1) describes, inter alia, certain(3-halo-1-(pyridin-3-yl)-1H-pyrazol-4-yl)amides and carbamates and theiruse as pesticides. The route to prepare such compounds involved thepreparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine by the directcoupling of 3-bromopyridine with 3-chloropyrazole. The 3-chloropyrazolewas prepared by a) treating 1H-pyrazole with 2 dimethylsulfamoylchloride and sodium hydride to provideN,N-dimethyl-1H-pyrazole-1-sulfonamide, b) treating theN,N-dimethyl-1H-pyrazole-1-sulfonamide with perchloroethane and n-butyllithium to provide 3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide, andc) removing the N,N-dimethylsulfonamide from3-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide with trifluoroaceticacid to give the 3-chloropyrazole.

The disclosed process produces low yields, relies on a starting materialthat is difficult to prepare (3-chloropyrazole) and provides a productthat is difficult to isolate in a pure form. It would be desirable tohave a process for preparing 3-(3-chloro-1H-pyrazol-1-yl)pyridine thatavoids these problems.

SUMMARY

The present invention provides such an alternative by cyclizing3-hydrazinopyridine.dihydrochloride with a dialkyl maleate to providealkyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a), bychlorinating to provide alkyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b),by oxidizing to provide alkyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c), by convertingthe ester to the carboxylic acid by hydrolysis to provide3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(10d), and by removing the carboxylic acid by a decarboxylationreaction. Thus, the present invention concerns a process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b),

which comprises

a) treating 3-hydrazinopyridine.dihydrochloride

with a dialkyl maleate

wherein

-   -   R represents (C₁-C₄) alkyl,        in a (C₁-C₄) aliphatic alcohol at a temperature of about 25° C.        to about 100° C. in the presence of an alkali metal (C₁-C₄)        alkoxide to provide an alkyl        5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a)

wherein R is as previously defined;

b) treating the alkyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate(10a) with a chlorinating reagent in an inert organic solvent at atemperature of about 25° C. to about 100° C. to provide an alkyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b)

wherein R is as previously defined;

c) treating the alkyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b)with an oxidant in an inert organic solvent at a temperature of about25° C. to about 100° C. to provide an alkyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c)

wherein R is as previously defined;

d) treating the alkyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c) with aqueoushydrochloric acid at a temperature of about 25° C. to about 100° C. toprovide 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acidhydrochloride (10d)

e) treating 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acidhydrochloride with copper(II) oxide in a polar aprotic solvent at atemperature of about 80° C. to about 140° C.

DETAILED DESCRIPTION

The present invention provides an improved process for preparing3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b), by cyclizing3-hydrazinopyridine.dihydrochloride with a dialkyl maleate to provide analkyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a), bychlorinating to provide an alkyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b),by oxidizing to provide an alkyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c), by convertingthe ester to the carboxylic acid by hydrolysis to provide3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(10d), and by removing the carboxylic acid by a decarboxylationreaction.

In the first step, 3-hydrazinopyridine.dihydrochloride is treated with adialkyl maleate in a (C₁-C₄) aliphatic alcohol at a temperature of about25° C. to about 100° C. in the presence of an alkali metal (C₁-C₄)alkoxide to provide an alkyl5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a). Whilestoichiometric amounts of 3-hydrazinopyridine.dihydrochloride anddialkyl maleate are required, it is often convenient to use about a 1.5fold to about a 2 fold excess of dialkyl maleate. The cyclization is runin the presence of an alkali metal (C₁-C₄) alkoxide base. It is oftenconvenient to use about a 2 fold to about a 5 fold excess of base. Thecyclization is performed in a (C₁-C₄) aliphatic alcohol. It is mostconvenient that the alkoxide base, the alcohol solvent and the ester ofthe maleate be the same, for example, sodium ethoxide in ethanol withdiethyl maleate.

In a preferred reaction, sodium ethoxide in an anhydrous ethanol areintroduced into a reaction vessel and3-hydrazinopyridine.dihydrochloride is added. The mixture is stirred anddiethyl maleate is added. The mixture is heated at about 60° C. untilmost of the 3-hydrazinopyridine has reacted. The mixture is allowed tocool and the excess base is neutralized with acid. The crude ethyl5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a) is convenientlyisolated and purified by standard techniques.

In the second step, the alkyl5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a) is treated with achlorinating reagent in an inert organic solvent at a temperature ofabout 25° C. to about 100° C. to provide alkyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b).Suitable chlorinating reagents include phosphoryl chloride (phosphorousoxychloride) and phosphorus pentachloride. Phosphoryl chloride ispreferred. It is often convenient to use about a 1.1 fold to about a 10fold excess of the chlorinating reagent. The chlorination is performedin an organic solvent that is inert to the chlorinating reagent.Suitable solvents include nitriles such as acetonitrile. With phosphorylchloride as the chlorinating reagent, acetonitrile is a preferredsolvent.

In a preferred reaction, ethyl5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a) and acetonitrileare mixed with phosphoryl chloride and the mixture is heated to about60° C. for 2 hours. After the reaction is determined to be complete, thereaction is cooled to room temperature and diluted with water. Thereaction mixture is then neutralized with base and extracted. The alkyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b)can be purified by standard techniques.

In the third step, alkyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b) istreated with an oxidant in an organic solvent at a temperature of about25° C. to about 100° C. to provide alkyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c). Suitableoxidants include manganese (IV) oxide and sodium persulfate/sulfuricacid. It is often convenient to use about a 1.5 fold to about a 15 foldexcess of oxidant. The oxidation is performed in an organic solvent thatis inert to the oxidant. Suitable solvents include nitriles such asacetonitrile. With manganese (IV) oxide or sodium persulfate/sulfuricacid as the oxidant, acetonitrile is a preferred solvent.

In a preferred reaction, ethyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b)and acetonitrile are mixed with manganese(IV) oxide and the mixture isheated at about 60° C. until the reaction is completed. The ethyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c) isconveniently isolated and purified by standard techniques.

In the fourth step, alkyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c) is thenconverted to the desired3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(10d) by treatment in aqueous hydrochloric acid at a temperature ofabout 25° C. to about 100° C. While stoichiometric amounts of reagentsare required, it is often convenient to use an excess of reagent withrespect to the alkyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate(10c). Thus, aqueous hydrochloric acid is used in large excess as thereaction medium.

In a preferred reaction, a mixture of ethyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c) and aqueoushydrochloric acid are mixed and heated to about 90° C. After completionof the reaction, the mixture is cooled and diluted with an organicsolvent. The resulting solution is concentrated. The3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(10d) can be purified by standard techniques such as filtration.

3-Chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(10d) is then converted to the desired3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) by decarboxylation in thepresence of copper (II) oxide in polar solvents at a temperature fromabout 80° C. to about 140° C. It was surprisingly discovered that thisdecarboxylation only occurs in the presence of copper (II) oxide.Several known decarboxylation agents from the literature such as, forexample, hydrochloric acid (See Example 4), sulfuric acid (See “CE-5”),and palladium (II) trifluoroacetate/trifluoroacetic acid (See “CE-5”)did not yield the desired product.

In a preferred reaction, a mixture of3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(10d) and copper(II) oxide are mixed in an organic solvent and heated toabout 120° C. It is often convenient to use less than stoichiometricamounts of copper(II) oxide. The decarboxylation is performed in a polaraprotic organic solvent. Suitable solvents includeN,N′-dimethylformamide. After completion of the reaction, the mixture iscooled, diluted with ammonium hydroxide, and extracted. The3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) can be purified by standardtechniques.

The following examples are presented to illustrate the invention.

EXAMPLES 1. Preparation of ethyl5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a)

A 4-neck round bottomed flask (250 mL) was charged with sodium ethoxide(21 wt % in ethanol, 56 mL, 192 mmol).3-Hydrazinopyridine.dihydrochloride (10.0 g, 55.0 mmol) was added,causing an exotherm from 20° C. to 32° C. The reaction was allowed tocool to 20° C. and diethyl maleate (13.4 mL, 82.0 mmol) was added, andthe reaction was heated at 60° C. for 3 hours (h). The reaction wascooled to 20° C. and quenched with acetic acid. The reaction mixture wasdiluted with water (100 mL) and extracted with ethyl acetate (3×100 mL).The combined organics were concentrated to dryness and the residue waspurified by flash column chromatography using ethyl acetate as eluent tothe title compound as a blue oil (6.60 g, 51%): ¹H NMR (400 MHz,DMSO-d₆) δ 10.40 (s, 1H), 8.40-8.26 (m, 1H), 8.19 (dd, J=4.4, 1.6 Hz,1H), 7.47-7.21 (m, 2H), 4.77 (dd, J=9.8, 2.1 Hz, 1H), 4.22 (qd, J=7.1,1.7 Hz, 2H), 3.05 (dd, J=17.0, 9.8 Hz, 1H), 1.99 (s, 1H), 1.25 (t, J=7.1Hz, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ 170.37, 146.60, 142.60, 137.28,123.54, 121.94, 65.49, 61.32, 32.15, 20.72, 13.94; ESIMS m/z 236([M+H]⁺).

2. Preparation of ethyl3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b)

A 3-neck round bottomed flask (100 mL) was charged with ethyl5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (8.50 g, 36.1 mmol) andacetonitrile (40 mL). Phosphoryl chloride (4.05 mL, 43.4 mmol) wascharged and the reaction was heated at 60° C. for 2 h. The reaction wascooled to 20° C. and water (100 mL) was added. Sodium carbonate wasadded to adjust pH to 8 and the mixture was extracted with ethyl acetate(3×100 mL). The organic layers were concentrated to dryness and theresidue was purified by flash column chromatography using 30-80% ethylacetate/hexanes as eluent to provide the title compound as a yellow oil(7.30 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ 8.30 (dd, J=2.9, 0.8 Hz, 1H),8.17 (dd, J=4.7, 1.4 Hz, 1H), 7.38 (ddd, J=8.4, 2.8, 1.4 Hz, 1H), 7.18(ddd, J=8.4, 4.7, 0.7 Hz, 1H), 4.79 (dd, J=12.4, 6.9 Hz, 1H), 4.24 (qd,J=7.1, 1.1 Hz, 2H), 3.55 (dd, J=17.7, 12.4 Hz, 1H), 3.33 (dd, J=17.8,6.9 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 169.65,141.90, 141.33, 141.09, 135.13, 123.53, 120.37, 62.89, 62.35, 42.45,14.03; ESIMS m/z 254 ([M+H]⁺).

3. Preparation of ethyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c)

A 3-neck round bottomed flask (100 mL) was charged with ethyl3-chloro-1-(pyridin-3-yl)-1H-dihydropyrazole-5-carboxylate (2.00 g, 7.88mmol) and acetonitrile (20 mL). Manganese(IV) oxide (3.43 g, 39.4 mmol)was added. The reaction was stirred at 60° C. for 18 h. Additionalmanganese(IV) oxide (3.43 g, 39.4 mmol) was added and the reaction wasstirred at 80° C. for 6 h. The mixture was filtered through a Celite®pad and the pad was rinsed with ethyl acetate (20 mL). The combinedfiltrates were concentrated to dryness and the residue was purified byflash column chromatography using 10-60% ethyl acetate/hexanes. The purefractions were concentrated to dryness to afford a white solid afterdrying (1.84 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ 8.75-8.64 (m, 2H), 7.79(ddd, J=8.2, 2.6, 1.5 Hz, 1H), 7.42 (ddd, J=8.2, 4.8, 0.8 Hz, 1H), 6.98(s, 1H), 4.27 (q, J=7.1 Hz, 2H), 1.27 (t, J=7.1 Hz, 3H); ¹³C NMR (101MHz, CDCl₃) δ 157.90, 149.88, 147.01, 141.41, 136.24, 135.27, 133.34,123.11, 111.97, 61.87, 13.98; ESIMS m/z 252 ([M+H]⁺).

Alternate synthetic route to ethyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c)

A vial (20 mL) was charged with ethyl3-chloro-1-(pyridin-3-yl)-1H-dihydropyrazole-5-carboxylate (0.500 g,1.97 mmol) and acetonitrile (5 mL). Sodium persulfate (0.799 g, 2.96mmol) was added, followed by sulfuric acid (0.733 g, 7.88 mmol)(Exotherm!). The reaction was heated at 60° C. for 18 hours. Thereaction was cooled to 20° C. and poured into water (20 mL). The mixturewas treated with sodium carbonate to achieve pH 9 and extracted withethyl acetate (2×20 mL). The organic layers were concentrated to aresidue, which was purified by flash column chromatography using 50%ethyl acetate/hexanes as eluent to provide the title compound as a whitesolid (0.280 g, 56%).

4. Preparation of 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylicacid hydrochloride (10d)

A 3-neck round bottomed flask (100 mL) was charged with ethyl3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (0.200 g, 0.795mmol) and hydrochloric acid (37%, 4 mL). The reaction was heated at 90°C. for 18 hours and allowed to cool to 20° C. Dioxane (5 mL) was addedto the resulting suspension and was concentrated to dryness. Dioxane (5mL) was added and the suspension was concentrated again to afford awhite solid. Dioxane (5 mL) was added and the resulting suspension wasstirred for 1 hour at 20° C. The solid was filtered and the solid wasrinsed with dioxane (2 mL). The filter cake was dried under vacuum at20° C. to afford the title compound as a white solid (0.218 g, 100%): ¹HNMR (400 MHz, DMSO-d₆) δ 9.05 (dd, J=2.5, 0.7 Hz, 1H), 8.84 (dd, J=5.3,1.4 Hz, 1H), 8.41 (ddd, J=8.3, 2.5, 1.4 Hz, 1H), 7.88 (ddd, J=8.3, 5.2,0.7 Hz, 1H), 7.26 (s, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 158.71, 146.00,143.44, 140.36, 137.76, 137.00, 136.83, 125.19, 111.71.

4. Preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b)

3-Chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(1.00 g, 3.65 mmol) was stirred in N,N′-dimethylformamide (10 mL).Copper (II) oxide (0.0580 mg, 0.730 mmol) was added and the reaction washeated at 120° C. for 16 hours, at which point the reaction was ˜20%complete. Additional copper (II) oxide (0.112 g, 1.46 mmol) was addedand the reaction was stirred for 5 hours. The mixture was diluted withammonium hydroxide and water and extracted with ethyl acetate. Theorganic layer was washed with lithium chloride (15%) and concentrated toprovide an orange solid. The residue was purified by flash columnchromatography using ethyl acetate as eluent and the pure fractions wereconcentrated to afford the desired product as a white solid (0.481 g,69.7%): mp: 66-68° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.93 (d, J=27 Hz, 1H),8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91(d, J=2.6 Hz, 1H), 7.47-7.34 (m, 1H), 6.45 (d, J=2.6 Hz, 1H); ¹³C NMR(101 MHz, CDCl₃) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41,124.01, 108.0.

COMPARATIVE EXAMPLES Example CE-53-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (5b)

Attempted Decarboxylation with Sulfuric Acid:

3-Chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(1.00 g, 2.50 mmol) was dissolved in warm sulfolane (12.5 mL). Sulfuricacid (1.35 mL, 25.0 mmol) was added and the reaction mixture was heatedto 100° C. After stifling for 1 hour, LCMS indicated that the reactiondid not occur. The reaction was further heated at 130° C. for 2 hours,at which point LCMS indicated no change. Additional sulfuric acid (4 mL)was added and the reaction was heated at 150° C. for 2 hours, at whichpoint LCMS showed a new major peak that did not correspond to desiredproduct.

Attempted decarboxylation with palladium(II)trifluoroacetate/trifluoroacetic acid:3-Chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride(1.00 g, 2.50 mmol) was dissolved in a mixture of dimethylsulfoxide(0.625 mL) and N,N′-dimethylformamide (11.9 ml). Trifluoroacetic acid(1.93 ml, 25.0 mmol) was added followed by the addition of palladium(II)trifluoroacetate/trifluoroacetic acid (0.332 g, 1.00 mmol). The reactionwas heated at 100° C. overnight, at which time LCMS indicated that areaction had occurred but no desired product had been formed.

BIOLOGICAL EXAMPLES Example A Bioassays on Green Peach Aphid (“GPA”)(Myzus persicae) (MYZUPE.)

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of leaves, and the death of various tissues. It isalso hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress andzucchini among other plants. GPA also attacks many ornamental crops suchas carnations, chrysanthemum, flowering white cabbage, poinsettia androses. GPA has developed resistance to many pesticides.

Several molecules disclosed herein were tested against GPA usingprocedures described below.

Cabbage seedling grown in 3-in pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-5-GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four pots with individual seedlings were used for eachtreatment. Test compounds (2 mg) were dissolved in 2 mL of acetone/MeOH(1:1) solvent, forming stock solutions of 1000 ppm test compound. Thestock solutions were diluted 5× with 0.025% Tween 20 in water to obtainthe solution at 200 ppm test compound. A hand-held aspirator-typesprayer was used for spraying a solution to both sides of the cabbageleaves until runoff. Reference plants (solvent check) were sprayed withthe diluent only containing 20% by volume acetone/MeOH (1:1) solvent.Treated plants were held in a holding room for three days atapproximately 25° C. and ambient relative humidity (RH) prior tograding. Evaluation was conducted by counting the number of live aphidsper plant under a microscope. Percent Control was measured by usingAbbott's correction formula (W. S. Abbott, “A Method of Computing theEffectiveness of an Insecticide” J. Econ. Entomol 18 (1925), pp.265-267) as follows.Corrected % Control=100*(X−Y)/X

where

X=No. of live aphids on solvent check plants and

Y=No. of live aphids on treated plants

The results are indicated in the table entitled “Table 1: GPA (MYZUPE)and sweetpotato whitefly-crawler (BEMITA) Rating Table”.

Example B Bioassays on Sweetpotato Whitefly Crawler (Bemisia tabaci)(BEMITA.)

The sweetpotato whitefly, Bemisia tabaci (Gennadius), has been recordedin the United States since the late 1800s. In 1986 in Florida, Bemisiatabaci became an extreme economic pest. Whiteflies usually feed on thelower surface of their host plant leaves. From the egg hatches a minutecrawler stage that moves about the leaf until it inserts itsmicroscopic, threadlike mouthparts to feed by sucking sap from thephloem. Adults and nymphs excrete honeydew (largely plant sugars fromfeeding on phloem), a sticky, viscous liquid in which dark sooty moldsgrow. Heavy infestations of adults and their progeny can cause seedlingdeath, or reduction in vigor and yield of older plants, due simply tosap removal. The honeydew can stick cotton lint together, making it moredifficult to gin and therefore reducing its value. Sooty mold grows onhoneydew-covered substrates, obscuring the leaf and reducingphotosynthesis, and reducing fruit quality grade. It transmittedplant-pathogenic viruses that had never affected cultivated crops andinduced plant physiological disorders, such as tomato irregular ripeningand squash silverleaf disorder. Whiteflies are resistant to manyformerly effective insecticides.

Cotton plants grown in 3-inch pots, with 1 small (3-5 cm) true leaf,were used at test substrate. The plants were placed in a room withwhitely adults. Adults were allowed to deposit eggs for 2-3 days. Aftera 2-3 day egg-laying period, plants were taken from the adult whiteflyroom. Adults were blown off leaves using a hand-held Devilbliss sprayer(23 psi). Plants with egg infestation (100-300 eggs per plant) wereplaced in a holding room for 5-6 days at 82° F. and 50% RH for egg hatchand crawler stage to develop. Four cotton plants were used for eachtreatment. Compounds (2 mg) were dissolved in 1 mL of acetone solvent,forming stock solutions of 2000 ppm. The stock solutions were diluted10× with 0.025% Tween 20 in water to obtain a test solution at 200 ppm.A hand-held Devilbliss sprayer was used for spraying a solution to bothsides of cotton leaf until runoff. Reference plants (solvent check) weresprayed with the diluent only. Treated plants were held in a holdingroom for 8-9 days at approximately 82° F. and 50% RH prior to grading.Evaluation was conducted by counting the number of live nymphs per plantunder a microscope. Pesticidal activity was measured by using Abbott'scorrection formula (see above) and presented in Table 1.

TABLE 1 GPA (MYZUPE) and sweetpotato whitefly-crawler (BEMITA) RatingTable % Mortality Rating 80-100 A More than 0- Less than 80 B Not TestedC No activity observed in this bioassay D

TABLE 2 Example Compound BEMITA MYZUPE 10a B B 10b B B

What is claimed is:
 1. A process for preparing 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b),

which comprises a) treating 3-hydrazinopyridine.dihydrochloride

with a dialkyl maleate

wherein R represents (C₁-C₄) alkyl, in a (C₁-C₄) aliphatic alcohol at a temperature of about 25° C. to about 100° C. in the presence of an alkali metal (C₁-C₄) alkoxide to provide an alkyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a)

wherein R is as previously defined; b) treating the alkyl 5-oxo-2-(pyridin-3-yl)pyrazolidine-3-carboxylate (10a) with a chlorinating reagent in an inert organic solvent at a temperature of about 25° C. to about 100° C. to provide an alkyl 3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b)

wherein R is as previously defined; c) treating the alkyl 3-chloro-1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (10b) with an oxidant in an inert organic solvent at a temperature of about 25° C. to about 100° C. to provide an alkyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c)

wherein R is as previously defined; d) treating the alkyl 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylate (10c) with aqueous hydrochloric acid at a temperature of about 25° C. to about 100° C. to provide 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride (10d)

e) treating 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid hydrochloride with copper(II) oxide in a polar aprotic solvent at a temperature of about 80° C. to about 140° C.
 2. The process of claim 1 in which for step a) the dialkyl maleate is diethyl maleate, the (C₁-C₄) aliphatic alcohol is ethanol and the alkali metal (C₁-C₄) alkoxide is sodium ethoxide.
 3. The process of claim 1 in which for step b) the chlorinating reagent is phosphoryl chloride and the inert organic solvent is acetonitrile.
 4. The process of claim 1 in which for step c) the oxidant is manganese (IV) oxide and the inert organic solvent is acetonitrile.
 5. The process of claim 1 in which for step e) the polar aprotic solvent is N,N′-dimethylformamide. 